全文获取类型
收费全文 | 4156篇 |
免费 | 246篇 |
国内免费 | 1篇 |
出版年
2022年 | 21篇 |
2021年 | 56篇 |
2020年 | 23篇 |
2019年 | 44篇 |
2018年 | 60篇 |
2017年 | 57篇 |
2016年 | 97篇 |
2015年 | 111篇 |
2014年 | 166篇 |
2013年 | 246篇 |
2012年 | 250篇 |
2011年 | 273篇 |
2010年 | 160篇 |
2009年 | 150篇 |
2008年 | 244篇 |
2007年 | 223篇 |
2006年 | 224篇 |
2005年 | 226篇 |
2004年 | 265篇 |
2003年 | 257篇 |
2002年 | 235篇 |
2001年 | 84篇 |
2000年 | 75篇 |
1999年 | 71篇 |
1998年 | 55篇 |
1997年 | 51篇 |
1996年 | 41篇 |
1995年 | 57篇 |
1994年 | 27篇 |
1993年 | 39篇 |
1992年 | 54篇 |
1991年 | 42篇 |
1990年 | 34篇 |
1989年 | 38篇 |
1988年 | 29篇 |
1987年 | 32篇 |
1986年 | 37篇 |
1985年 | 31篇 |
1984年 | 27篇 |
1983年 | 22篇 |
1982年 | 14篇 |
1981年 | 12篇 |
1980年 | 15篇 |
1979年 | 15篇 |
1978年 | 14篇 |
1977年 | 11篇 |
1976年 | 13篇 |
1975年 | 12篇 |
1972年 | 11篇 |
1970年 | 9篇 |
排序方式: 共有4403条查询结果,搜索用时 15 毫秒
971.
Expression of long-form N-acetylglucosamine-6-O-sulfotransferase 1 in human high endothelial venules
Fujiwara M Kobayashi M Hoshino H Uchimura K Nakada T Masumoto J Sakai Y Fukuda M Nakayama J 《The journal of histochemistry and cytochemistry》2012,60(5):397-407
Two members of the N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST) family, GlcNAc6ST-1 and GlcNAc6ST-2, function in the biosynthesis of 6-sulfo sialyl Lewis X-capped glycoproteins expressed on high endothelial venules (HEVs) in secondary lymphoid organs. Thus, both enzymes play a critical role in L-selectin-expressing lymphocyte homing. Human GlcNAc6ST-1 is encoded by a 1593-bp open reading frame exhibiting two 5' in-frame methionine codons spaced 141 bp apart. Both resemble the consensus sequence for translation initiation. Thus, it has been hypothesized that both long and short forms of GlcNAc6ST-1 may be present, although endogenous expression of either form has not been confirmed in humans. Here, the authors developed an antibody recognizing amino acid residues between the first two human GlcNAc6ST-1 methionines. This antibody specifically recognizes the long form of the enzyme, a finding validated by Western blot analysis and immunofluorescence cytochemistry of HeLa cells misexpressing long and/or short forms of human GlcNAc6ST-1. Using this antibody, the authors carried out immunofluorescence histochemistry of human lymph node tissue sections and found endogenous expression of the long form of the enzyme in human tissue, predominantly in the trans-Golgi network of endothelial cells that form HEVs. 相似文献
972.
973.
CD45(low)c-Kit(high) cells have hematopoietic properties in the mouse aorta-gonad-mesonephros region
Long-term reconstituting hematopoietic stem cells first arise from the aorta of the aorta-gonad-mesonephros (AGM) region in a mouse embryo. We have previously reported that in cultures of the dispersed AGM region, CD45(low)c-Kit(+) cells possess the ability to reconstitute multilineage hematopoietic cells, but investigations are needed to show that this is not a cultured artifact and to clarify when and how this population is present. Based on the expression profile of CD45 and c-Kit in freshly dissociated AGM cells from embryonic day 9.5 (E9.5) to E12.5 and aorta cells in the AGM from E13.5 to E15.5, we defined six cell populations (CD45(-)c-Kit(-), CD45(-)c-Kit(low), CD45(-)c-Kit(high), CD45(low)c-Kit(high), CD45(high)c-Kit(high), and CD45(high)c-Kit(very low)). Among these six populations, CD45(low)c-Kit(high) cells were most able to form hematopoietic cell colonies, but their ability decreased after E11.5 and was undetectable at E13.5 and later. The CD45(low)c-Kit(high) cells showed multipotency in vitro. We demonstrated further enrichment of hematopoietic activity in the Hoechst dye-effluxing side population among the CD45(low)c-Kit(high) cells. Here, we determined that CD45(low)c-Kit(high) cells arise from the lateral plate mesoderm using embryonic stem cell-derived differentiation system. In conclusion, CD45(low)c-Kit(high) cells are the major hematopoietic cells of mouse AGM. 相似文献
974.
Shitara Y Tonohora Y Goto T Yamada Y Miki T Makino H Miwa M Komiya T 《Journal of biochemistry》2012,152(1):73-85
P5, one of the protein disulphide isomerase (PDI) family members, catalyses disulphide bond formation in proteins and exhibits molecular chaperone and calcium binding activities in vitro, whereas its physiological significance remains controversial. Recently, we have reported that P5 localizes not only in the ER but also in mitochondria, although it remains unclear so far about its physiological significance(s) of its dual localization. Here we report that H(2)O(2)- or rotenone-induced cell death is suppressed in MTS-P5 cells, which stably express P5 in mitochondria. H(2)O(2)-induced cell death in Saos-2 cells occurred, in large part, through caspase-independent and poly(ADP-ribose) polymerase (PARP)-dependent manner. In MTS-P5 cells challenged with H(2)O(2) treatment, PARP was still activated, whereas release of cytochrome c or apoptosis-inducing factor and intramitochondrial superoxide generation were suppressed. We also found that mitochondrial P5 was in close contact with citrate synthase and maintained large parts of its activity under H(2)O(2) exposure. These results suggest that mitochondrial P5 may upregulate tricarboxylic acid cycle and possibly, other intramitochondrial metabolism. 相似文献
975.
976.
I Kawamura S Maeda K Imamura T Setoguchi M Yokouchi Y Ishidou S Komiya 《The Journal of biological chemistry》2012,287(34):29101-29113
Hypertrophic maturation of chondrocytes is a crucial step in endochondral ossification, whereas abnormally accelerated differentiation of hypertrophic chondrocytes in articular cartilage is linked to pathogenesis of osteoarthritis. This cellular process is promoted or inhibited by bone morphogenetic protein (BMP) or transforming growth factor-β (TGF-β) signaling, respectively, suggesting that these signaling pathways cross-talk during chondrocyte maturation. Here, we demonstrated that expression of Tgfb1 was increased, followed by phosphorylation of Smad2, during BMP-2-induced hypertrophic maturation of ATDC5 chondrocytes. Application of a TGF-β type I receptor inhibitor compound, SB431542, increased the expression of Id1, without affecting the phosphorylation status of Smad1/5/8, indicating that the activated endogenous TGF-β pathway inhibited BMP signaling downstream of the Smad activation step. We searched for TGF-β-inducible effectors that are able to inhibit BMP signaling in ATDC5 cells and identified SnoN. Overexpression of SnoN suppressed the activity of a BMP-responsive luciferase reporter in COS-7 cells as well as expression of Id1 in ATDC5 cells and, subsequently, the expression of Col10a1, a hallmark of hypertrophic chondrocyte maturation. siRNA-mediated loss of SnoN showed opposite effects in BMP-treated ATDC5 cells. In adult mice, we found the highest level of SnoN expression in articular cartilage. Importantly, SnoN was expressed, in combination with phosphorylated Smad2/3, in prehypertrophic chondrocytes in the growth plate of mouse embryo bones and in chondrocytes around the ectopically existing hypertrophic chondrocytes of human osteoarthritis cartilage. Our results indicate that SnoN mediates a negative feedback mechanism evoked by TGF-β to inhibit BMP signaling and, subsequently, hypertrophic maturation of chondrocytes. 相似文献
977.
Shiga D Hamano Y Kamei M Funahashi Y Masuda H Sakaguchi M Ogura T Tanaka T 《Journal of biological inorganic chemistry》2012,17(7):1025-1031
The axial interactions of Cu(2+) in type 1 copper proteins control the physical characteristics of the proteins. We tuned the geometries of a de novo designed blue copper protein with a four-helical bundle structure. The designed protein axially bound various ligands, such as chloride, phosphate, sulfate, acetate, azide, and imidazole, to Cu(2+), exhibiting a blue or green color. The UV-vis spectral bands were observed at approximately 600?nm and approximately 450?nm, with the A (~450)/A (~600) ratios between 0.14 and 1.58. The stronger axial interaction shifted the geometry of the type 1 copper site from trigonal planar geometry (blue copper) toward a tetrahedral-like geometry (green copper). Resonance Raman spectral analyses showed that the phosphate-bound type had the highest-strength Cu-S bond, similar to that of plastocyanin. The chloride-bound type exhibited features similar to those of stellacyanin and nitrite reductase, and the imidazole-bound type exhibited features similar to those of azurin M121E mutant. 相似文献
978.
979.
T Sugimoto Y Shimazaki A Manaka T Tanikawa K Suzuki K Nanaumi Y Kaneda Y Yamasaki H Sugiyama 《Bioorganic & medicinal chemistry letters》2012,22(17):5739-5743
Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide derivatives with activities against resistant pathogens is urgently needed. A series of novel 6-O-(heteroaryl-isoxazolyl)propynyl 2-fluoro ketolides has been synthesized from erythromycin A. These compounds have shown very promising in vitro and in vivo antibacterial activities against key respiratory pathogens including erythromycin-susceptible/resistant strains. 相似文献
980.
Asakawa C Ogawa M Fujinaga M Kumata K Xie L Yamasaki T Yui J Fukumura T Zhang MR 《Bioorganic & medicinal chemistry letters》2012,22(11):3594-3597
N-(2-{3-[3,5-Bis(trifluoromethyl)]phenylureido}ethyl)glycyrrhetinamide (2), an ureido-substituted derivative of glycyrrhetinic acid (1), has been reported to display potent inhibitory activity for proteasome and kinase, which are overexpressed in tumors. In this study, we labeled this unsymmetrical urea 2 using [(11)C]phosgene ([(11)C]COCl(2)) as a labeling agent with the expectation that [(11)C]2 could become a positron emission tomography ligand for the imaging of proteasome and kinase in tumors. The strategy for the radiosynthesis of [(11)C]2 was to react hydrochloride of 3,5-bis(trifluoromethyl)aniline (4·HCl) with [(11)C]COCl(2) to possibly give isocyanate [(11)C]6, followed by the reaction of [(11)C]6 with N-(2-aminoethyl)glycyrrhetinamide (3). 相似文献